PROJECT SUMMARY ? OVERALL If there is one issue that unites the diverse and vocal community of families affected by autism spectrum disorder (ASD), it is the frustration that despite the hundreds of millions of dollars that have been spent on autism research, there are so few treatment options available to decrease the disabilities of their loved ones. The overarching goal of our proposed Center for the Development of Phenotype-Based Treatments of Autism Spectrum Disorder is to discover targets for effective treatments in groups of children with ASD with rigorously defined phenotypic characteristics. It has become abundantly clear that there are many causes and trajectories of ASD. Moreover, some of the most debilitating aspects of ASD are due to the serious co-morbid conditions such as anxiety, seizures and intellectual disability. Considering the broad range of clinical and behavioral features of ASD, it is unlikely that a single treatment will correct all of these problems. This proposal is based on the premise that identifying clinically meaningful subtypes of ASD will facilitate the analysis of etiologies and the development of more effective therapeutics. The Specific Aims for the Center include: Aim #1: To use enhanced clinical evaluations of children with ASD, particularly those with intellectual disability, to better characterize the sub-group that exhibits clinically significant anxiety. Proper diagnosis and effective treatment holds the promise of a much-improved quality of life for these children. Aim #2: To conduct a 16-week randomized comparative treatment trial of Behavioral Intervention for Anxiety in Children with Autism (BIACA), sertraline, and pill placebo in youth with ASD. Aim #3: To use fMRI to investigate neural predictors of treatment efficacy, markers of treatment-induced change, and signatures of anxiety sub-types defined in Aim 1. Aim #4: To carry out behavioral, neuroimaging and electrophysiological analyses of a newly recruited group of children (2-3 1/2-years-old) with ASD and brains that are disproportionately enlarged relative to body size. The major goal of this aim is to increase our understanding of the cognitive functions and brain systems that are so impacted as to lead to a poorer prognosis for these children. This would inform the design of more targeted behavioral interventions. While there is no evidence that these children have less access to standard behavioral therapies, it has become clear that they constitute an ASD phenotype that benefits less from standard interventions. How to treat these children is not yet clear and the Center endeavors to fill this gap. Aim #5: To generate an iPSC patient resource from a subset of the children that are investigated in Aim #4. Lines of iPSCs for each subject will be differentiated into neural progenitor cells, oligodendrocytes and microglial cells to identify gray and white matter contributions to the development of enlarged brains. The cell lines will also be studied by RNA-sequencing to identify gene networks and signaling mechanisms that are altered. These studies may provide additional targets for pharmacological treatment of this form of ASD.